Acyclovir requires three phosphorylation steps for activation. It is converted first to the monophosphate derivative by viral thymidine kinase, and then to the diphosphate and triphosphate derivatives by the host’s cellular enzymes (human cell kinases).

What is the mechanism of action of acyclovir?

1) Acyclovir first needs to be bioactivated via phosphorylation. The guanosine is added and then phosphorylated (a phosphate group is added). The first phosphorylation is by a viral kinase. The other two phosphorylations are by human kinases.

2) Acyclovir competes with guanosine triphosphate.

3) Acyclovir inhibits viral DNA synthesis.

What phosphorylates?

Kinases phosphorylate

What is a polymerase?

A polymerase is an enzyme whose central function is associated with polymers of nucleic acids, such as RNA and DNA.

The primary function of a polymerase is the polymerization of new DNA or RNAagainst an existing DNA or RNA template in the processes of replication and transcription.

Why is acyclovir selective in its actions?

Because viral kinase is required for its initial phosphorylation, acyclovir is selectively activated and accumulates only in infected cells.

1) Competitive inhibition with deoxyGTP (Guanosine Triphosphate) for the viral DNA polymerase, resulting in binding to the DNA template as an irreversible complex.

2) Chain termination following incorporation into the viral DNA.

What are mechanisms of resistance to acyclovir?

Resistance to acyclovir can develop in HSV or VZV through alteration (mutations) in either the viral thymidine kinase or the DNA polymerase.

Which medications work against very resistant strains of viruses?

Agents such as:

foscarnet (antiviral for CMV)

cidofovir (antiviral for CMV)

trifluridine (antiviral for HSV & VZV)

do not require activation by viral thymidine kinase. As a result, they are active against the most prevalent acyclovir-resistant strains.

Are there any adverse effects or toxicities of acyclovir?

Acyclovir is generally well tolerated. Nausea, diarrhea, and headache have occasionally been reported.

How is acyclovir selective?

Acyclovir is highly selective for infected human cells where the first enzyme for bioactivation can be found because it is provided by the virus (which is inside the cell, thus making the human cell "infected"). This is good because it lowers the toxicity of the drug.

Antivirals for the treatment of Cytomalovirus (CMV) Infections

Ganciclovir

Valganciclovir

Cidofovir

Foscarnet

What is ganciclovir?

Ganciclovir is an acyclic guanosine analog.

How does ganciclovir compare to acyclovir?

Its activity against CMV is up to 100 times greater than that of acyclovir.

Ganciclovir triphosphate (the active form of the drug) competitively inhibits viral DNA polymerase and causes termination of viral DNA elongation.

What is the mechanism of action for ganciclovir?

1) Ganciclovir first needs to be bioactivated via triphosphorylation. The guanosine is added and then phosphorylated (a phosphate group is added). The first phosphorylation is by a viral kinase. The other two phosphorylations are by human kinases.

2) Ganciclovir competes with the natural substrate to inhibit the viral DNA polymerase.

3) Ganciclovir inhibits viral DNA synthesis.

What are the mechanisms of resistance to ganciclovir?

1) Altered Viral Kinase: Mutations in UL97, resulting in decreased levels of the active triphosphorylated form of ganciclovir. Isolates with these mutations are not cross-resistant to cidofovir or foscarnet. In other words, cidofovir and foscarnet will still work, even when ganciclovir does not.

Is there cross resistance with ganciclovir and cidofovir or foscarnet?

Mutations in UL97, resulting in decreased levels of the active triphosphorylated form of ganciclovir. Isolates with these mutations are not cross-resistant to cidofovir or foscarnet. In other words, cidofovir and foscarnet will still work, even when ganciclovir does not.

What toxicities are associated with ganciclovir?

Myelosuppression, particularly neutropenia (more common with IV than with oral administration)

Retinal detachment (in patients with CMV retinitis)

Antivirals for the treatment of Cytomalovirus (CMV) Infections

Ganciclovir

Valganciclovir

Cidofovir

Foscarnet

What is cidofovir?

Cidofovir is a cytosine nucleotide analog.

Is cidofovir associated with guanosine or cytosine?

Cidofovir is a cytosine analog.

Is cidofovir a nucleoside or a nucleotide?

Cidofovir is a nucleotide because it already has the phosphate group on it...it just needs two more phosphates to convert the drug to its active form.

What is the mechanism of action for cidofovir?

Following phosphorylation, cidofovir acts both as a potent inhibitor of and as an alternative substrate for viral DNA polymerase, competitively inhibiting DNA synthesis and becoming incorporated into the viral DNA chain.

How does cidofovir compare to ganciclovir?

In contrast to ganciclovir, phosphorylation of cidofovir to the active diphosphate is independent of viral enzymes.

What toxicities are present with cidofovir?

Dose-dependent nephrotoxicity

Decreased intraocular pressure

Which toxicity of cidofovir is dose dependent?

nephrotoxicity is dose dependent

Antivirals for the treatment of Cytomalovirus (CMV) Infections

Ganciclovir

Valganciclovir

Cidofovir

Foscarnet

What is foscarnet?

Foscarnet (phosphonoformic acid) is an inorganic

pyrophosphate analog.

Is foscarnet a nucleoside or a nucleotide?

No...foscarnet is neither a nucleoside nor a nucleotide. Rather, it is just a phosphate.

No...foscarnet will not compete with the natural substrate. Foscarnet does not compete. Rather, it is an inhibitor, not a competitor.

Does foscarnet require phosphorylation for activation?

No...foscarnet does not require phosphorylation for activation.

What mechanisms of resistance are associated with foscarnet?

Resistance to foscarnet in HSV and CMV is due to point mutations in the DNA polymerase gene and is associated with prolonged or repeated exposure to the drug. Mutations in the HIV-1 reverse transcriptase gene have also been reported.

In other words, Target Modification is taking place in resistance that alters where the drugs can bind.

What is resistance in foscarnet associated with?

Point mutations, which is the mechanism of resistance seen with foscarnet, are associated with prolonged or repeated exposure to the drug.

What toxicities are there with foscarnet?

Nephrotoxicity

Anemia

CNS toxicity (headache, hallucinations, seizures)

What is therapy for the HIV-1 virus called?

Antiretroviral therapy

What is the difference between a regular virus and a retrovirus?

regular virus: makes DNA from RNA (like human cells do)

retrovirus: makes RNA from DNA (exact opposite of a regular virus)

Are there any pharmacologic treatments available for HIV-1 infection?

A large number of antiretroviral drugs are available for the treatment of HIV-1 infection.

Should antiretrovial therapy be used in combination or not?

Monotherapy with any one agent should be avoided because of the need for maximal potency to inhibit viral replication and to avoid premature development of resistance.

Optimization of adherence, tolerability, and convenience is also important in selecting the antiretroviral drugs for therapy.

How many drugs does HAART therapy consist of?

HAART therapy consists of at least threeantiviral drugs.

Why is monitoring therapy important in HAART therapy?

Given that many patients will experience at least one treatment failure, close monitoring of viral load and CD4 cell counts and the use of drug resistance testing are critical to trigger appropriate changes in therapy.

Yes...nucleosidescompete for the catalytic site and then inhibit. NRTIs fall into this category, and are therefore nucleosides.

Do NRTIs need to be bioactivated?

Yes...NRTIs are considered prodrugs because they need to be bioactivated. Each one of the NRTIs requires intracytoplasmic activation by phosphorylation to the triphosphate form. Phosphorylation of the NRTIs is catalyzed by human cell kinases.

What is the NRTIs mechanism of action?

The reverse transcriptase enzyme has two active (catalytic) sites:

1) The RNase H (RNA-cleaving) active site

2) The DNA polymerase (DNA-synthesizing) active site

Both activities (RNA-cleaving and DNA-synthesizing) are needed to reverse-transcribe HIV’s RNA-based genomic material into DNA.

NRTIs bind to the DNA polymerase catalytic site of the reverse transcriptase enzyme. As a result, they competitively inhibit the DNA polymerase activity of the enzyme and can also be incorporated into the growing viral DNA chain to cause termination.

NRTIs bind to the DNApolymerase catalytic site of the reverse transcriptase enzyme.

Do NRTIs compete for the active site?

Yes...NRTIs bind to the DNA polymerase catalytic site of the reverse transcriptase enzyme. As a result, they competitively inhibit the DNA polymerase activity of the enzyme and can also be incorporated into the growing viral DNA chain to cause termination.

Must the NRTIs be phosphorylated for activation?

Each one of the NRTIs requires intracytoplasmic activation by phosphorylation to the triphosphate form. Phosphorylation of the NRTIs is catalyzed by human cell kinases.

Do the NRTIs need a viral enzyme for activation?

No...NRTIs are catalyzed by human cell kinases.

Are there any mechanisms of resistance present in the NRTIs?

Resistance to the NRTIs is caused by viral mutations.

Is there cross resistance among the NRTIs?

Cross-resistance between the NRTIs has been demonstrated. Recall that a mutation in the DNA polymerase will cause resistance. Because all the NRTIs bind to the same site on the DNA polymerase, there is 100% cross resistance because if one can't bind, none can bind....all because they have the same binding site.

What are toxicities of NRTIs?

Lactic acidemia and severe hepatomegaly have been reported with the use of the NRTIs, alone or in combination with other antiretroviral drugs.

What was the first antiviral drug to be approved by the FDA?

Zidovudine (Azidothymidine; AZT)

What is zidovudine?

Zidovudine is a deoxythymidine analog.

Why is zidovudine used in antiretrovirus therapy?

It has been shown to decrease the rate of clinical disease progression and prolong survival in HIV-infected individuals.

Should zidovudine be used during pregnancy?

When administered during pregnancy, during labor, and to the neonate, zidovudine has also been shown to reduce the rate of vertical (mother-to-newborn) transmission of HIV.

What is vertical transmission of HIV?

Vertical transmission is when an HIV-positive motherpasses the virusonto thenewborn.

If AZT therapy is given for the prevention of transmission to a neonate, what are the chances of preventing transmission?

There is a 30% decrease of preventing transmission from the HIV transmission from mom to the neonate. It's not a lot, but it's better than nothing.

What types of resistance are found among AZT?

As with other NRTIs, viral resistance to AZT may limit its clinical efficacy.

High-level resistance to AZT is generally seen in strains with three or more mutations.

Withdrawal of AZT exposure may permit the reversion of AZT-resistant HIV-1 isolates to the susceptible wild-type phenotype.

Can resistance to AZT be reversed?

Withdrawal of AZT exposure may permit the reversion of AZT-resistant HIV-1 isolates to the susceptible wild-type phenotype.

What are toxicities associated with AZT?

Myelosuppression (resulting in anemia or neutropenia) is the most common adverse effect of AZT.

The NNRTIs bind directly to sites on the HIV-1 reverse transcriptase, resulting in inhibition of RNA- and DNA-dependentDNA polymerase activities.

How do NNRTIs compare to NRTIs?

Although both NNRTIs and NRTIs inhibit the same enzyme, they work differently.

NNRTIs

- bind directly to the reverse transcriptase enzyme

- don't require phosphorylation for activation

- don't compete with natural substrates

NRTIs

- don't bind directly to reverse transcriptase enzyme

- require phosphorylation for activation

- compete with the natural substrate

Do the NNRTIs have the same binding site as the NRTIs?

The binding sites for the NNRTIs are near to but distinct from the binding site for the NRTIs (i.e., they are near to the DNA polymerase catalyticsite of the enzyme). Binding of the NNRTIs blocks the DNA polymerase activity by disrupting the DNA polymerase catalytic site of the enzyme.

What exactly do NNRTIs do?

Binding of the NNRTIs blocks the DNA polymerase activityby disrupting the DNA polymerase catalytic site of the enzyme.

Do NNRTIs require phosphorylation to be active?

Unlike the NRTIs, the NNRTIs do not compete with nucleoside triphosphatesand do not require phosphorylation to be active.

Do NNRTIs compete for the catalytic site?

Unlike the NRTIs, the NNRTIs do not compete with nucleoside triphosphates and do not require phosphorylation to be active.

Should NNRTIs be used in combination or not?

Resistance to a NNRTI is rapid with monotherapy, so combination therapy is suggested.

Which mechanisms of resistance are found in NNRTIs?

Resistance to a NNRTI is rapid with monotherapy and is associated with specific viral mutations.

Is there any cross resistance with NRTIs?

There is no cross-resistance between the NNRTIs and the NRTIs or the protease inhibitors.

Is Nevirapine normally used in combination?

Nevirapine, a NNRTI, is used mainly as a component of a combinationantiretroviral regimen.

What enzymes in the liver does nevirapine affect?

Nevirapine is extensively metabolized by CYP3A4 in the liver (ie, it is a substrate for CYP3A4).

It is also an inducer of CYP3A metabolism (drug

interactions).

What are toxicities associated with nevirapine?

Severe and life-threatening skin rashes, including toxic epidermal necrolysis, have occurred during nevirapine therapy; in such cases,

nevirapine therapy should be discontinued.

Fulminant (sudden and severe enough to be life threatening) hepatitis may occur within the

first 6 weeks of initiation of therapy; serial monitoring of liver function tests is recommended.

Antiretroviral Agents (HIV): Protease Inhibitors

Saquinavir

Ritonavir

Lopinavir

Indinavir

Nelfinavir

Amprenavir

Tipranavir

Fosamprenavir

Darunavir

Atazanavir

What is the protease enzyme responsible for in the HIV infection?

During the later stages of the HIV growth cycle, the Gag and Gag-Pol gene products are translated into polyproteins and then become immature budding particles.

The protease enzyme is responsible for cleaving these precursor molecules to produce the final structural proteins of the mature virion core.

What do protease inhibitors do?

Recall that the protease enzyme is like the scissors....it cuts off the virus when mature so it can go infect other cells. In other words, the protease enzyme converts non-infectious immature viral particles into mature viral particles by cleaving polyproteins (which the virus needs to mature) into smaller functional proteins.

Tesamorelin (Egrifta®), a growth hormone-releasing factor administered as a once-daily injection, was approved by the FDA for the treatment of lipodystrophy in patients receiving antiretroviral therapy.

Do protease inhibitors cause changes in lipid and carbohydrate metabolism?

Allprotease inhibitors are substrates for CYP3A4in the liver (ie, they are metabolized by CYP3A4 in the liver). As a result, there is a great potential for drug-drug interactions.

Which enzyme do protease inhibitors inhibit?

In addition, protease inhibitors are CYP3A4 inhibitors as well. Consequently, these agents can cause decreased clearance and increased plasma levels of other substrate drugs. Protease inhibitors should not be administered concurrently with agentsthat are extensively metabolized by CYP3A4.

What is the most potent CYP3A4 inhibitor of the protease inhibitors?

Ritonavir

Antiretroviral Agents (HIV): Protease Inhibitors

Saquinavir

Ritonavir

Lopinavir

Indinavir

Nelfinavir

Amprenavir

Tipranavir

Fosamprenavir

Darunavir

Atazanavir

What is Ritonavir?

Ritonavir is an inhibitor of HIV-1 and HIV-2proteases.

Why would Ritanovir be given concurrently with other protease inhibitors?

Since ritonavir is an inhibitor of CYP3A4, concurrent administration of ritonavir with other protease inhibitors results in increased plasma levels of these agents because it decreases the rate of metabolism of these drugs (there will be no enzyme to degrade them with ritonavir inhibiting the CYP3A4 enzyme).

These pharmacokinetic interactions between ritonavir and other protease inhibitors have been exploited to permit:

more convenient dosing (ie, improve patient compliance)

improve tolerability

enhance efficacy

What is an example of ritanovir concurrent therapy?

For example, administration of saquinavir

in combination with a low (subtherapeutic) dose of ritonavir has allowed clinicians to decrease the frequency of saquinavir dosing and resulted in improved antiviral efficacy of saquinavir and decreased GI side effects that are typically associated with saquinavir therapy.

In this combination, the subtherapeutic dose of ritonavir inhibits theCYP3A4-mediated metabolism of saquinavir, thereby resulting in increased exposure (blood levels) to saquinavir.

The high saquinavir plasma levels that are produced by this combination maintain potent viral suppression as well as provide a pharmacologic barrier to the emergence of resistance.

Besides the saquinavir-ritonavir combination, what are other examples?

Other examples of the use of ritonavir in a combination with another protease inhibitor are the lopinavir/ritonavir and the tipranavir/ritonavir combinations.

What is the most potent CYP3A4 inhibitor?

Ritonavir is the most potent CYP3A4 inhibitor.

What is "PI Boosting"?

PI boosting, which stands for "Protease Inhibitor Boosting" is a unique trick used by practitioners in fighting the HIV virus. Rather than directly inhibit the protease enzymes, CYP3A4 inhibitors, like Ritonavir can be used to boost plasma levels of other protease inhibitors, which in essence, makes the effect of protease inhibitors stronger.

Blocking the liver enzyme that metabolizes drugs (CYP3A4) would enhance the protease inhibitors plasma levels because the protease inhibitors won't be degraded as quickly by the CYP3A4 enzyme.

Antiretroviral Agents (HIV): Fusion Inhibitors

Enfuvirtide (T-20)

What is fusion?

In terms of viral replication, fusion is a pre-requisite for viral entry.

Fusion is when the viral envelope melts into the cell membrane. It begins with binding of glycoproteins gp 41 located in the viral envelope.

What is Enfuviritide?

Enfuvirtide is a synthetic 36-amino-acid peptide.

Of interest, this drug was developed in North Carolina.

How is Enfuviritide administered?

Enfuvirtide is administered subcutaneously, in combination with other antiretroviral agents, in patients with persistent HIV-1 replication despite ongoing therapy.

Is Enfuvirtide administered in combination or not?

Enfuvirtide is administered subcutaneously, in combination with other antiretroviral agents, in patients with persistent HIV-1 replication despite ongoing therapy.

In what type of HIV-1 is Enfuvirtide administered?

Enfuvirtide is administered subcutaneously, in combination with other antiretroviral agents, in patients with persistent HIV-1 replication despite ongoing therapy.

What is the mechanism of action for Enfuviritide?

Enfuvirtide is a fusion inhibitor that blocks entry of the virus into the cell. It binds to the gp41 subunit of the viral envelope glycoprotein, preventing the conformational changes required for the fusion of the viral and cellular membranes.

Is there viral resistance present with Enfuvirtide?

Viral resistance to enfuvirtide can occur and it is being investigated.

Is there any cross resistance between enfuvirtide and other drugs?

There is no cross-resistance between enfuvirtide and the other currently available antiretroviral drug classes.

What are toxicities associated with enfuvirtide?

The most common side effects of enfuvirtide therapy are local injection site reactions. Hypersensitivity reactions of varying severity may occur and recur on rechallenge.

Antiretroviral Agents (HIV): CCR5 Antagonists

Maraviroc

What is CCR5?

CCR5 are co-receptors on CD4 lymphocytes (the cells that HIV attacks) that the virus needs to enter the cell.

If the infection uses only CCR5, we call it a "tropic" infection. For example, a strain that uses only CCR5 would be called: CCR5-tropic HIV-1 detectable disease.

In other words, HIV uses one of two co-receptors known as Chemokine Receptor 5 (CCR5) and Chemokine Receptor 4 (CXCR4) to enter human CD4 cells of the immune system and infect them.

In general, viruses that use CCR5predominate in early disease; as CD4 cell counts decline in more advanced disease, patients begin to harbor viruses that use CXCR4 for cell entry.

Patients with HIV that preferentially uses CCR5 are classified as having CCR5-tropic disease.

What would an infection be called if it uses more than CCR5?

An HIV infection that uses more than CCR5 would be called a "dual" or "mixed tropism" infection. For instance, some strains use both CCR5 and CXCR4.

What is Maraviroc (Selzentry®)?

Maraviroc is a new anti-HIV drug approved by the FDA in August 2007.

It is indicated for use in combination with other antiretroviral drugs to treat adults with CCR5-tropic HIV-1-detectable disease.

Should Maraviroc be used in combination?

It is indicated for use in combination with other antiretroviral drugs to treat adults with CCR5-tropic HIV-1-detectable disease.

Maraviroc binds to and blocksCCR5 on CD4 cells. As a result, it is able to block the entry of HIV into CD4 cells and prevent the infection.

What type of infection must an HIV patient have in order for Maraviroc to be effective?

Maraviroc is effective only in patients with CCR5-tropic disease; it is ineffective against HIV that uses both receptors (dual/mixed tropism) or that preferentially uses CXCR4 for cell entry (CXCR4-tropic disease).

How can a clinician determine the tropism of an HIV patient?

Patients must undergo a screening testto determine the tropism of their HIV infection (CCR5, CXCR4, or dual-tropic) before initiating treatment with maraviroc.

However, the test (Trofile®) may fail to detect the presence of small numbers (<0.3%) of the CXCR4-tropic virus, which would proliferate and cause maraviroc to fail. The Trofile test will work 100% of the time as long as the CXCR-4 virus affects at least 0.3% of the viral population.

What toxicities are associated with Maraviroc?

Treatment with maraviroc has been associated with an increased incidence of hepatotoxicity (it has a boxed warning for potential hepatotoxicity). Symptoms of a systemic allergic reaction may occur beforehepatotoxicity develops.

Treatment with maraviroc has also been associated with cardiovascular events such as myocardial ischemia and infarction and postural hypotension. It should be used with caution in patients with increased risk of cardiovascular disease.

Treatment with maraviroc may increase a patient’s

risk of developing infections and malignancy.

What symptom may precede hepatotoxicity when taking Maraviroc?

Treatment with maraviroc has been associated with an increased incidence of hepatotoxicity (it has a boxed warning for potential hepatotoxicity). Symptoms of a systemic allergic reaction may occur beforehepatotoxicity develops.

Which cardiovascular events are increased with Maraviroc?

Treatment with maraviroc has been associated with

cardiovascular events such as myocardial ischemia and infarction and postural hypotension.

It should be used with caution in patients with increased risk of cardiovascular disease.

Will taking Maraviroc increase the risk of cancer and infection?

Yes. Treatment with maraviroc may increase a patient’s risk of developing infections and malignancy.

3) rhabdomyolysis (Rhabdomyolysis is the breakdown of muscle fibers resulting in the release of muscle fiber contents (myoglobin) into the bloodstream)

Anti-Hepatitis Therapy

Lamivudine

Adefovir

Interferon Alfa

Pegylated Interferon Alfa

Ribavirin

Entecavir

Telbivudine

Tenofovir

Emtricitabine

How prevalent are Hepatitis infections?

The prevalence of infections caused by hepatitis B

virus (HBV) and hepatitis C virus (HCV) is very high worldwide.

The morbidity (the rate of incidence of disease) and mortality (the rate of deaths associated with the disease) associated with these infections reflect a great and critical needfor improved anti-hepatitis therapies.

Will anti-hepatitis therapy cure infection?

Similar to the antiretroviral therapy, available anti-hepatitis therapy is suppressiverather than curative.

What is Adefovir?

Like tenofovir, adefovir is a nucleotide analog of adenosine monophosphate.

What type of infection is Adefovir used for?

Adefovir has been approved for the treatment of HBV infection.

How long must Adefovir be administered?

Studies have shown that adefovir therapy results in significant suppression of HBV replication

and improvement in liver histology and fibrosis.

However, serum HBV DNA reappearedfollowing cessation of therapy.

What is the mechanism of action for Adefovir?

1) Adefovir is phosphorylated by cellular kinases to the active diphosphate metabolite.

2) Following activation, it competitively inhibitsHBV DNA polymerase

3) Adefovir then inserts itself via incorporation into the viral DNA

4) This inhibition results in chain termination

Does Adefovir need to be phosphorylated to be active?

Yes. Adefovir is similar to tenofavir...it must be phosphorylated to become activated.

Does Adefovir need viral kinases to be activated?

No. Adefovir is phosphorylated by cellular kinases (not viral kinases) to the active phosphorylated form with two phosphate groups.

Does Adefovir compete for the active site?

Yes. Adefovir competitively inhibitsHBV DNA polymerase.

What is the final consequence of Adefovir?

Once Adefovir has incorporated itself into viral DNA, it causes chain termination which will inhibit the virus.

What toxicities are associated with Adefovir?

Adefovir therapy is associated with a dose dependent nephrotoxicity. The risk of nephrotoxicity may rise in patients with preexisting renal dysfunction or in those treated for longer durations.

As with the antiretroviral nucleoside analogs (NRTIs) the following can occur:

1) lactic acidosis (Lactic acidosis is when lactic acid builds ups in the bloodstream faster than it can be removed. Lactic acid is produced when oxygen levels in the body drop.)

2) severe hepatomegaly may occur. (An enlarged liver).

What are two risk factors that may increase the chances of nephrotoxicity when taking Adefovir?

Adefovir therapy is associated with a dose dependentnephrotoxicity.

The risk of nephrotoxicity may rise in patients with preexisting renal dysfunction or in those treated for longer durations.

What other class of drugs share toxicities with Adefovir?

As with the antiretroviral nucleoside analogs (NRTIs) the following can occur:

1) lactic acidosis (Lactic acidosis is when lactic acid builds ups in the bloodstream faster than it can be removed. Lactic acid is produced when oxygen levels in the body drop.)

2) severe hepatomegaly may occur. (An enlarged liver).

What is Interferon Alfa (IFN-a)?

Interferons (IFNs) are a group of cytokines. They are endogenous proteins that exert complex antiviral, immunomodulatory, and antiproliferative activities through cellular metabolic processes involving the synthesis of both RNA and protein.

What type of infection does Interferon Alfa treat and how is it administered?

Interferon alfa preparations are available for the treatment of both HBV and HCV infections; they are administered SC or IM.

3) cytokines can then inhibit different steps in the viral mechanism of action

Does Interferon alfa need to be used in combination?

Interferon alfa can be used alone for HBV and HCV, or it is also used in combination with Ribaviron.

What type of variation of interferon drugs are available?

Pegylated interferon alfa preparations (where a linear or branched polyethylene glycol (PEG) moiety is attached to the interferon molecule by a covalent bond) are available.

Is there any advantage to using pegylated interferon alfa preparations?

In comparison with the nonpegylated interferon alfa preparations, the pegylated products have:

1) substantially longer half-lives

2) slower clearance

3) steadier serum concentrations

All of these things allow for less frequent dosing.

What is the mechanism of action for Interferons (IFNs)?

Interferons (IFNs) are a group of cytokines. They are endogenous proteins that exert complex antiviral, immunomodulatory, and antiproliferative activities through cellular metabolic processes involving the synthesis of both RNA and protein.

They bind to specific membrane receptors (cytokine receptors) on the cell surface and initiate a series of intracellular events that include enzyme induction, suppression of cell proliferation, immunomodulatory activities, and inhibition of viral replication.

Following binding to specific cellular receptors (cytokine receptors), IFNs activate the JAK-STAT signal-transduction pathway and lead to the nuclear translocation of a cellular protein complex that binds to genes containing an IFN-specific response element. This leads to the synthesis of over 24 antiviral proteins that contribute to viral resistance mediated at different stages of viral penetration.

A major effect of IFN-induced antiviral proteins is inhibition of viral protein synthesis for many viruses. A given virus may be inhibited at several steps, and the principal inhibitory effect differs among virus families.

Remember the general idea of the picture below: interferon alfa will lead to anti-viral proteins expressed which will inhibit several steps in the viral mechanism of action. The predominant effect varies from one virus to another, but in most viruses, the anti-viral proteins inhibit step #2 below, which is translation.

Is there viral resistance associated with interferons (IFNs)?

Certain viruses are able to resist the antiviral effects of IFNs by blocking production or activity of selected IFN-inducible antiviral proteins.

For example, resistance to IFN therapy in HCV infections is attributed to a number of mechanisms including inhibition of the IFN-induced protein kinase.

Do Interferons have any other effects (either good or bad) besides the direct antiviral effects?

Yes. In addition to their direct antiviral effects, IFNs are also able to modify the immune response to viral infections.

The GOOD: For example, IFN-induced expression of MHC antigens (major histocompatibility antigens) may contribute to the antiviral actions of IFNs by enhancing the lytic effects of cytotoxic T-lymphocytes.

The BAD: Conversely, IFNs may mediate some of the systemic symptoms associated with viral infections and contribute to immunologically mediated tissue damage in certain viral diseases.

Are there any toxicities associated with Interferons (IFNs)?

Common side effects include a flu-like syndrome within 6 hours after dosing that tends to resolve

How does one deal with a common side effect of flu-like symptoms that happens with Interferons?

Common side effects include a flu-like syndrome within 6 hours after dosing that tends to resolveupon continued administration. Therefore, just continue on with therapy.

What are some contraindications with Interferons (IFNs)?

There are many contraindications to interferon

therapy, including:

psychosis

severe depression

symptomatic heart disease

uncontrolled seizures

Can alfa interferons be used during pregnancy?

Alfa interferons are abortifacient in primates and should not be administered during pregnancy.

What is Ribavirin?

It is a guanosine analog that requires intracellular activation. It is phosphorylated by host cell enzymes to the active triphosphate.

Must Ribavirin be phosphorylated to become activated?

Yes. Ribavirin must be phosphorylated by the host cell enzymes to the active triphosphate form.

Ribavirin is used in combination with what drug?

Ribavirin is used in combination with interferon alfa for the treatment of HCV infection.

When is Ribavirin used?

Because Ribavirin is used in combination with interferon alfa for the treatment of HCV, they won't put you on Ribavirin combination unless the single therapy doesn't work.

What is the mechanism of action for Ribavirin?

Its mechanism of action has not been fully elucidated. However, it appears to be involved in the following:

1) It interferes with thesynthesis of guanosine triphosphate.

2) It inhibitscapping of viral mRNA.

3) It inhibitsviral RNA-dependent RNA polymerase.

What are the three anti-viral effects of Ribavirin?

1) It interferes withthe synthesis ofguanosine triphosphate.

2) It inhibitscapping of viral mRNA.

3) It inhibitsviral RNA-dependent RNA polymerase.

What are the toxicities associated with Ribavirin?

Dose-dependent hemolytic anemia and depression.

Are the toxicities of Ribavirin dose dependent?

Dose-dependenthemolytic anemia and depression.

Can Ribavirin be used during pregnancy?

It is contraindicated during pregnancy (it is teratogenic in animals and mutagenic in mammalian cells).

Anti-Influenza Agents

Amantadine & Rimantadine

Zanamivir & Oseltamivir

What are the Adamantanes?

Amantadine & Rimantadine

What are Amantadine & Rimantadine?

Amantadine (Symmetrel®) and its derivativerimantadine (Flumadine®) are cyclic amines.

Between Amantadine & Rimantadine, which is more active?

Rimantadine is four to ten times more active than

amantadine in vitro.

Recall in vitro means not in a living organism, but in a controlled environment, like a test tube.

What do Amantadine & Rimantadine treat?

Influenza type A. However, resistance of influenza A virus to both agents has increased substantially in recent years.

What is the mechanism of action of amantadine and rimantadine?

Amantadine and rimantadine inhibit the uncoatingof the viral RNA of influenza A viruswithin infected hostcells, thus preventing its replication. For some influenza A strains, they also inhibit viral assembly.

The primary target for both agents is the M2 protein within the viral membrane, which makes these two agents highly specific against influenza A virus (influenza B virus contains a different protein in its membrane).

By binding to and inhibiting the function of the M2protein (an ion channel), these drugs are able to inhibit the acid-mediated dissociation of the viral ribonucleoprotein complex early in viral replication (i.e., inhibiting viral uncoating) and alter hemagglutinin processing (by inducing conformational changes in hemagglutinin during its intracellular transport) later in replication (i.e., inhibiting viral assembly).

Remember, the virus cannot replicate unless the coat is removed in the genome. That is why inhibiting viral uncoating will block the virus from replicating.

What is the primary target for both Amantadine and Rimantadine?

The primary targetfor both agents is the M2 protein within the viral membrane, which makes these two agents highly specific against influenza A virus (influenza B virus contains a different protein in its membrane).

What are the two main things that Amantadine and Rimantadine inhibit?

inhibit viral uncoating

inhibit viral assembly (in some selected strains)

Are Amantadine and Rimantadine considered specific?

Yes. The primary target for both agents is the M2 protein within the viral membrane, which makes these two agents highly specific against influenza A virus (influenza B virus contains a different protein in its membrane).

Why is Amantadine & Rimantadine currently not recommended for use?

Resistance of influenza A virusto both agents has increased substantially in recent years, to the point that this combination is currently not recommended for use.

Can the resistant Hepatits A virus be transferred from patient to patient?

Yes. Resistance, caused by mutation, rapidly develops in treated patients. Transmission of resistant virus to household contacts has been reported.

Is there cross resistance with Amantadine and Rimantadine?

Yes. These drugs share cross resistance.

Do Amantadine and Rimantadine share cross resistance with the other combination anti-influenza drugs?

No. Cross-resistance to zanamivir and oseltamivirdoes not occur.

Do Amantadine and Rimantadine share cross-susceptibility?

Yes. Both drugs share cross-susceptibility?

What is the difference between cross-susceptibility and cross-resistance?

cross-susceptibility is when the virus can be either susceptible or resistant to drugs that work the same way. In the case of Amantadine and Ramantidine, then, influenza A would be either susceptible to both or resistant to both because they both work on the same M2 protein.

cross-resistanceis when the virus figures out how to change its mechanism of action to get around one drug, other drugs that work the same way won't work either. For example, in the case of Amantadine and Rimantadine, when the virus changes the M2 protein to avoid Amantadine, then Rimantadine won't work either.

Cross Susceptibility vs. Cross Resistance

Cross-susceptibilitymeans that if rimantadine is effective against a particular viral strain, then amantadine is also effective against the same strain.

Cross-resistancemeans that if a viral strain is resistant to rimantadine, it is also going to be resistant to amantadine.

What are toxicities associated with Amantadine & Rimantadine?

CNS toxicity (e.g., nervousness, lightheadedness, difficulty in concentrating). The CNS side effects are more frequent with amantadine.

Serious neurotoxic reactions, occasionally fatal,

may be associated with high amantadine plasma levels (1-5 mg/mL).

What dose of amantadine is considered high enough to cause serious neurotoxic reactions?

Amantadine is more toxic than Rimantadine because the CNS side effects more frequent with amantadine. Also because serious neurotoxic reactions, occasionally fatal, may be associated with high amantadine plasma levels (1-5 mg/mL).

Can Amantadine & Rimantadine be used during pregnancy?

Amantadine is teratogenic in rodents; birth defects have been reported after exposure during pregnancy.

What are Neuraminidase Inhibitors?

Zanamivir & Oseltamivir

What is neuraminidase?

Neuraminidase is an essential viral glycoprotein for viral release.

What type of infection do zanamivir and oseltamivir treat?

Zanamivir (Relenza®) and oseltamivir (Tamiflu®) are active against both influenza Aand influenza B.

Both agents have been approved for prophylaxis (prevention) or treatment of acute uncomplicated influenza infection.

When should zanamivir and/or oseltamivir be administered?

When administered for a 5-day coursewithin 36-48 hoursafter the onset of symptoms, use of either agent shortens the severity and duration of illness and may decrease the incidence of respiratory complications in children and adults.

The earlier they are started, the more effective they are in treating influenza.

Besides shortening the severity and duration of the flu virus, what other symptom can zanamivir and oseltamivir decrease?

Administration may decrease the incidence of respiratory complications in children and adults

How do zanamivir and oseltamivir differ from amantadine and rimantadine?

Unlike amantadine and rimantadine (which just treat influenza A), zanamivir (Relenza®) and oseltamivir (Tamiflu®) are active against both influenza A and influenza B.

Also, unlike amantadine and rimantadine (which are not recommended for treatment because of resistance), zanamivir (Relenza®) and oseltamivir (Tamiflu®) are the current recommended drugs for treatment or prophylaxis of influenza.

How are zanamivir and oseltamivir administered?

Zanamivir is administered via oral inhalation; oseltamivir is an orally administered prodrug that is activated in the gut and liver. Both drugs are also available in IV formulations.

Which drug, zanamivir or oseltamivir, must be bio-activated in the gut and the liver?

Oseltamivir is an orally administered prodrug that is activated in the gut and liver.

Are zanamivir and oseltamivir useful in the hospital setting? Are they used to prevent or treat nosocomial infections?

In hospitalized patients with the flu, both drugs have been shown to reduce the duration of hospitalization and therisk of death. They may also decrease viral shedding and the risk of spread to contacts even when started more than 48 hours after the onset of illness.

How effective, percantage-wise, are zanamivir and oseltamivir for prophylaxis?

Both drugs are about 70%-90% effective for prophylaxis after exposure to influenza A or B.

If prophylactically treating a patient, when should zanamivir or oseltamivir be administered?

They should be given within 48 hours after a household exposure or other close contact with an influenza virus-infected person.

Is there any viral resistance to zanamivir or oseltamivir?

Yes. Viral resistance to this class of drugs has been reported in both A and B strains of the influenza virus.

Viral resistance, mainly to oseltamivir, is associated with a mutation in the viral neuraminidase (target modification).

Is there any cross resistance between zanamivir and oseltamivir and any other previous drug class?

No. There is no cross resistance between these and any other previous drug class.

Can someone receive zanamivir and oseltamivir with the flu vaccine?

Inactivated flu vaccines are not affected by antiviral drug therapy.

However, antivirals may interfere with the efficacy of the live-attenuated intranasal flu vaccine (FluMist®); they should be stoppedat least 48hours before and should not be started for at least 2 weeksafterFluMist administration.

What is the mechanism of action for zanamivir and oseltamivir?

Zanamivir and oseltamivir are inhibitors of the viral neuraminidase enzyme.

Zanamivir can cause cough, nasal and throat irritation; bronchospasm in patients with reactive airway disease has also been reported. It is generally not recommended for use in patients with asthma or COPD.

Zanamivir is contraindicated for patients with what condition?

Zanamivir is generally not recommended for use in patients with asthma or COPD.

What toxicities are associated with oseltamivir?

Potential side effects of oseltamivir include headache, nausea and vomiting. Taking the drug with food may reduce the incidence of GI effects.

What might be a good patient education counseling point with oseltamivir and why?

Potential side effects of oseltamivir include headache, nausea and vomiting. Taking thedrug with foodmay reduce the incidence of GI effects.

Is there any association with oseltamivir and neuropsychiatric effects in children or adolescents?

Neuropsychiatric events, including self-injury, delirium, and hallucinations, have occurred in some children and adolescents treated with oseltamivir, but causation has not been established (i.e., the data increasingly points to the influenza infection, not oseltamivir, as the cause of these events).

What is the only emergency use anti-flu drug available?

In 2009, the FDA issued an ‘emergency use authorization’ for the neuraminidase inhibitorperamivir.

The FDA authorized the use of peramivir in hospitalized adults or children with confirmed or suspected pandemic 2009 H1N1 influenza infection who cannot take or are not responding to treatment with oseltamivir or zanamivir.

Can peramivir be used in children?

Yes. The FDA authorized the use of peramivir in hospitalized adults or children with confirmed or suspected pandemic 2009 H1N1 influenzainfection who cannot take or are not respondingto treatment with oseltamivir or zanamivir.

If there is resistance to peramivir, there might also be resistance to what drug?

Many clinical isolates resistant to oseltamivir have, however, also been resistant to peramivir.

Is there viral resistance with peramivir?

Yes. Many clinical isolates resistant to oseltamivir have, however, also been resistant to peramivir.

How do we know which viral strains in the US are actually susceptible and not susceptible to drugs we have available?

Susceptibility of the circulating influenza strains to antiviral drug therapy varies from one strain to anotherandfrom one flu season to another.

In recent years, however, susceptibility of circulating influenza strains has evolved rapidly and treatment recommendations have changed during the same flu season.